PBM-MAP-VPE Drug Monograph: Ecallantide
Ecallantide (Kalbitor®)
National Drug Monograph
December 2010
VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives
The purpose of VHA PBM-MAP-VPE drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current.
Executive Summary
Indications: Ecallantide (Kalbitor®), a plasma kallikrein inhibitor, is indicted for the treatment of acute attacks of hereditary angioedema (HAE) in patients 16 years of age.
Efficacy: In two randomized, double-blind, placebo-controlled trials (EDEMA3, EDEMA4) of patients presenting within 8 hours of acute symptoms of HAE, ecallantide 30 mg subcutaneously improved the endpoints of change from baseline in the mean symptom complex severity score (0=normal; 1=mild; 2=moderate; 3=severe) compared to placebo (EDEMA3: median -1.0 [mean -0.88] vs. -0.5 [-0.51], P=0.01; EDEMA4: median -1.0 [mean -0.8] vs.0 [ -0.4], P=0.01) and the change from baseline in treatment outcome score (100=significant improvement; 50=improvement; 0=same; -50=worsening; -100=significant worsening) compared to placebo (EDEMA3: median 50.0 [mean 46.8] vs. 0 [21.3], P=0.004; EDEMA4: median 50.0 [mean 53.4] vs. 0 [8.1], P=0.003); both endpoints evaluated at 4 hours post treatment. The effect of treatment with ecallantide was maintained through 24 hours.
Safety: The product information for ecallantide includes a Boxed Warning for anaphylaxis; occurring in 2.7% of 187 patients treated with ecallantide subcutaneously. It has been reported that 7.4% of patients developed anti-ecallantide antibodies, which may increase the risk for hypersensitivity reactions. The most frequently occurring adverse events in patients receiving ecallantide included headache, nausea, fatigue, diarrhea, upper respiratory tract infection, injection site reactions, nasopharyngitis, vomiting, pruritus, upper abdominal pain, and pyrexia.
Dose: Ecallantide should be administered as a dose of 30 mg (available as three single use vials of 10 mg/mL), administered as three subcutaneous injections of 10 mg/mL into the skin of the abdomen, thigh, or upper arm. The three injections may be at the same or different locations of the abdomen, thigh, or upper arm but should be separated by at least 2 inches and not in the location of the site where the attack is occurring. If the HAE attack continues despite the initial 30 mg dose ecallantide, an additional dose may be administered (same instructions apply) within 24 hours.
Conclusions: Ecallantide 30 mg, administered as three subcutaneous injections, was found to be effective in the treatment of acute HAE attacks as evaluated by a greater improvement from baseline in two patient-reported outcome measures (e.g., mean symptom complex severity score and treatment outcome score) compared to placebo. Treatment with ecallantide is reported to be well-tolerated, with a similar percentage of patients experiencing a treatment related adverse event as placebo. Due to the concerns of hypersensitivity reactions, ecallantide should be administered by a healthcare professional with medical support available for the management of anaphylaxis and HAE and would therefore not be appropriate for self-administration until additional safety data are available. Since ecallantide is not derived from human plasma as is C1 esterase inhibitor, there is no concern for viral transmission. However, ecallantide is a recombinant protein and seroconversion to anti-ecallantide antibodies has been reported, which may occur more frequently with increased exposure to the drug. In patients with HAE, treatment with ecallantide has not been compared to other therapies used for acute HAE attacks (e.g., C1 esterase inhibitor, fresh frozen plasma), and different efficacy parameters were used in the clinical trials. Therefore, selection of therapy for acute HAE attacks should take into consideration previous response, adverse effects, route of administration, and cost. Ecallantide has not been studied for short or long-term prophylaxis, or on-demand therapy in HAE, or in angioedema other than HAE.
Ecallantide (Kalbitor®)
National Drug Monograph
December 2010
VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives
Introduction1-6
Ecallantide (Kalbitor®, Dyax Corp) is a plasma kallikrein inhibitor, approved by the FDA December 1, 2009 for the treatment of acute attacks of hereditary angioedema (HAE) in patients 16 years of age.1
Hereditary angioedema is an autosomal dominant disorder caused by a deficiency in functional C1 inhibitor that has been estimated to affect approximately 1 in 50,000 persons (there are estimated to be approximately 6,000 patients in the United States with HAE). Typically, patients first present with symptoms in early childhood, with continued attacks for the duration of their lives. The frequency of attacks is variable, occurring on average every 1 to 2 weeks. Some patients will rarely experience an attack while others have them on a more frequent basis.2
The most common location for an acute attack is the skin or abdomen, with attacks of the skin most commonly involving the extremities, then face, genitals, and chest/neck. Symptoms may include swelling (most common in the hands, feet, arms, legs, and abdomen; less frequently involving the oropharynx) and a nonpruritic rash; often associated with tingling prior to the appearance of symptoms. Swelling may worsen over the first 24 hours then diminish over the next 2 to 3 days. Symptoms associated with the abdomen also include pain, nausea, vomiting, and hypotension due to a shift in fluid. Death has occurred with laryngeal angioedema. Triggers may include stress or trauma, including surgical or dental procedures; although, attacks may occur without a precipitating factor.2 Diagnosis can be made in a patient with a history of recurrent angioedema, and abdominal pain without urticaria. Measurement of C4 levels can be used to rule-out HAE, since nearly all patients with HAE will have decreased levels. Further testing may be conducted to evaluate the antigenic or functional C1 inhibitor level to determine the HAE type.2,3 Patients with HAE have a mutation in the C1 inhibitor gene and may be classified into type I (85% of patients) or type II (15%), the two main types of HAE that result in reduced levels of antigenic (type I) and functional (type I and II) levels of C1 inhibitor. Another type of familial angioedema has been described, primarily involving women during pregnancy or who received estrogen therapy (although, this form has also been found in men), that present with normal levels of antigenic and functional C1 inhibitor.2
Management of HAE includes recognition and avoidance of potential triggers, treatment of acute symptoms, and short and long-term prophylaxis.2-5 For the management of significant acute HAE attacks, use of C1 inhibitor has been recommended.2-5 Ecallantide, a kallikrein inhibitor has recently been approved by the FDA for treatment of acute HAE attacks.1,4 Fresh frozen plasma that contains C1 inhibitor has also been used for acute attacks although it is controversial as to whether treatment with fresh frozen plasma can exacerbate symptoms in some patients due to the potential for bradykinin production.2,3,6 Symptom control includes narcotic analgesics for abdominal pain, antiemetics, and hydration. Intubation may be necessary in patients with oropharyngeal involvement if closure of the airway occurs.2
Pharmacology/Pharmacokinetics1,7,8
C1 inhibitor is found in human blood and is a serine protease inhibitor that is involved in the regulation of the complement and intrinsic coagulation or contact system pathway, as well as the fibrinolytic system. C1 inhibitor forms a complex with the protease causing inactivation. C1 inhibitor helps regulate activation of the contact system, by inactivation of coagulation factor XIIa and kallikrein, preventing the conversion of High Molecular Weight (HMW) kininogen to bradykinin, which is thought to be responsible for the symptoms associated with HAE and increased vascular permeability. When there are low levels of functional C1 inhibitor, as in HAE, activation of the above pathways is not regulated.2
Ecallantide is a recombinant protein produced in Pichia pastoris (P pastoris) yeast cells. It is a selective, reversible inhibitor of plasma kallikrein that binds to kallikrein, decreasing the conversion of HMW kininogen to bradykinin, reducing the symptoms of acute HAE.1
Pharmacokinetic Parameters
/AUC
(ng*hr/mL)
/Cmax
(ng/mL) /Tmax
(hrs) /CL
(mL/hr/kg)
/Vd
(L)
/Half-life
(hrs)
Ecallantide 30 mg SC
/3017+402
/586+106
/2-3
/153+20
/26.4+7.8
/2.0+0.5
SC=subcutaneously; AUC=Area Under the Curve; Cmax=maximum plasma concentration; Tmax=Time to Cmax; CL=Plasma clearance; Vd=Volume of distribution
FDA Approved Indication1
Ecallantide (Kalbitor®, Dyax Corp.) is a plasma kallikrein inhibitor, approved for the treatment of acute attacks of HAE in patients 16 years of age.1
Potential Off-Label Uses1,7
This section is not intended to promote any off-label uses. Off-label use should be evidence-based. See VA PBM-MAP and Center for Medication Safety’s Guidance on “Off-label” Prescribing (available on the VA PBM Intranet site only).
Data are not available for the use of ecallantide for long-term prophylaxis, on-demand therapy, or short-term prophylaxis in patients with HAE. Ecallantide is currently being studied for treatment of patients with angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema and is not recommended until clinical trial results are available demonstrating benefit for this indication.
Current VA National Formulary Alternatives2,5
There are currently no VA National Formulary agents available that are indicated for the management of acute HAE.
The attenuated androgens (e.g., danazol) and antifibrinolytics (e.g., aminocaproic acid) are listed on the VA National Formulary and have been used in the management of acute HAE attacks, but due to the longer onset of action, are not typically recommended for treatment of acute attacks if other treatment options are available.
Dosage and Administration1,7
General Recommendations: Ecallantide is available in a carton that includes three 10 mg/mL single-use vials. Ecallantide should be protected from light and stored in the refrigerator at 36°F to 46°F (2°C to 8°C); if the vials are removed from the refrigerator, they should be kept at below 86°F (30°C) and used within 14 days or returned to the refrigerator. The solution should be colorless and clear and should not be used if any particulate material is visible or if the solution appears cloudy or is discolored. Aseptic technique should be used for administration. The contents of one 1 mL vial should be withdrawn into a syringe using a large bore needle; the needle should then be changed to one used for subcutaneous (SC) injection (27 gauge recommended). The contents of the syringe should be administered into the skin of the abdomen, thigh, or upper arm by SC injection. The procedure is to be repeated two additional times to administer a total dose of 30 mg (three 10 mg/mL single use vials). The three injections may be at the same or different locations of the abdomen, thigh, or upper arm but should be separated by at least 2 inches and not in the location of the site where the attack is occurring. If the HAE attack continues despite the initial 30 mg dose ecallantide, an additional dose may be administered (same instructions apply) within 24 hours.
Recommended Dose for Treatment of Acute HAE Attacks
Availability / DoseEcallantide 10 mg/mL single dose vials / 30 mg SC (three 10mg/mL injections), may repeat X 1 within 24 hours
Product Access
Ecallantide (Kalbitor®) is available through a single specialty pharmacy distributor. For more information refer to http://www.kalbitor.com/patient/access-program.html.
Efficacy7,9-11
A literature search was performed on PubMed/Medline using the search terms ecallantide and hereditary angioedema through 06 Aug 2010. The search was limited to clinical trials in humans that were published in the English language. Reference lists of review articles were searched for relevant clinical trials. All controlled trials published in peer-reviewed journals evaluating treatment with ecallantide SC in patients with hereditary angioedema in other than healthy subjects were included. Two Phase III clinical trials that evaluated ecallantide SC in the treatment of patients presenting with an acute attack of HAE (EDEMA39, EDEMA410) met these criteria and are discussed below (details provided in the Appendix). One published Phase II trial evaluating ecallantide administered by intravenous (IV) injection will not be reviewed.11
Efficacy Measures (Published Clinical Trials)9,10
Primary Endpoint
· Treatment outcome score (TOS) at 4 hours after initial treatment9
· Change from baseline in mean symptom complex severity (MSCS) score at 4 hours post treatment10
Secondary and Other Endpoints
· Change from baseline in MSCS score at 4 hours post treatment9
· TOS at 4 hours after initial treatment10
· Change from baseline in MSCS score and TOS at 24 hours after initial treatment9,10
· Time to significant improvement in overall response9
· Time to sustained improvement ( 45minutes) within 4 hours after treatment9
· Percent of patients with significant response maintained through 24 hours10
· Percent of patients with TOS 70 or 50 4 hours after initial treatment10
· Need for open-label ecallantide10
Clinical Trial Data7,9,10
The efficacy and safety of ecallantide 30 mg SC was evaluated in a phase III randomized, double-blind, placebo-controlled trial (EDEMA3) of 72 patients with documented HAE, with acute symptoms of any anatomic location that were of moderate to severe intensity , and who presented within 8 hours of the attack. If severe upper airway compromise (SUAC) occurred within 4 hours, patients could receive an open-label dose of ecallantide 30 mg SC; patients received additional treatment (e.g., fluids, pain relievers) during the 24 hours after study drug treatment as determined by the provider. Patients were evaluated during the 4 hours after initial treatment, and were seen for follow-up at 7, 30, and 90 days.9
Another randomized, double-blind, placebo-controlled trial (EDEMA4) evaluated ecallantide 30 mg SC in 96 patients with type I or II HAE, with acute symptoms of HAE of any anatomic location that were of moderate to severe intensity, and who presented within 8 hours of the attack. If SUAC occurred within 4 hours, patients could receive an open-label dose of ecallantide 30 mg SC and standard care; or if symptoms did not improve, resolve completely, or relapsed within 4 to 24 hours after the initial dose, patients could receive a single open-label dose (dose B) of ecallantide 30 mg SC and standard care. Patients could be discharged 4 hours after initial treatment, were contacted by phone at 2 days, and returned for a follow-up visit at 7 days.10
For both trials, a moderate attack included symptoms that adversely affected the patient’s activities of daily living (ADL) and for which treatment was sought; a severe attack was defined as necessary treatment due to the patient’s inability to perform ADLs due to their symptoms. Patient reported symptoms by affected location were identified at baseline and scored using the MSCS according to the following scale: 0=normal; 1=mild; 2=moderate; 3=severe. Symptoms were again rated at 4 and 24 hours post initial treatment. The endpoint evaluation was the change from baseline in MSCS score at 4 hours post treatment. Another patient-reported endpoint was the TOS at 4 hours after initial treatment. The TOS was a measure combining three elements of an acute HAE attack including identification of the symptom complex, evaluation of the severity of each symptom complex at baseline (scored as per the MSCS scale), and an evaluation of response of each symptom complex after treatment (scored as: 100=significant improvement; 50=improvement; 0=same; -50=worsening; -100=significant worsening). Additional endpoints included the change from baseline in MSCS score and TOS at 24 hours after initial treatment. In EDEMA3, the time to significant improvement in overall response and time to sustained improvement within 4 hours after treatment were also evaluated. The percent of patients with significant response maintained through 24 hours, the percent of patients with a TOS 70 or 50 4 hours after initial treatment, and need for open-label ecallantide were evaluated in EDEMA4.9,10